tbuckley/cabot-search huggingface dataset:
Sequential enfortumab vedotin (EV) after platinum-based chemotherapy in metastatic or locally advanced urothelial cancer: Complete response, bladder preservation and survival.
Authors: Putao Cen, Kok Hoe Chan, Steven Canfield, Tung Shu, Neha Maithel, Varaha Tammisetti
Journal: Journal of Clinical Oncology (2023)

529 Background: For metastatic or unresectable invasive urothelial cancer (UC), standard first-line platinum-based chemotherapy achieved progression-free survival (PFS) of 4–7 months. Complete response (CR) rate is &lt;10%. The minority of patients downstaged after chemotherapy followed by cystectomy still suffer from loss of bladder function and a high risk of recurrence. To improve PFS, CR, and bladder preservation, we explored the use of EV after platinum-based chemotherapy in patients with metastatic or locally advanced UC who desired bladder preservation. Methods: Patients with metastatic or locally advanced unresectable UC who desired bladder preservation and received EV after platinum-based chemotherapy were identified. CR was defined as no evidence of disease identified on both radiology (MRI+CT) and cystoscopy; PFS were calculated from the date of initial treatment (first-line chemotherapy) to the date of last follow-up/death or recurrence via Kaplan-Meier analysis. Results: A total of 12 patients were identified: median age was 69.5 years (range, 52–83); 10 (83%) were men; 9 (75%) partial response and 3 (25%) disease progression were observed from platinum-based chemotherapy. EV was given after platinum-based chemotherapy to all 12 patients who subsequently achieved 100% of response: CR was achieved in 7 (58%) patients, and 4 (33%) remained disease free without ongoing treatment, their disease-free survival (DFS) was 9 months (range, 4–18); 2 patients who achieved CR then recurred as carcinoma in situ (CIS), one of whom had a cystectomy with TisN0 confirmed on final pathology. 2 (17%) patients received radiation to bladder and nodal area. Eleven (92%) patients retained their bladders and no patients died. Median follow-up was 19 months (range, 3.4–53.6). The median duration of EV was 7.5 months (range, 2–20). One-year PFS with bladder intact was 83%. Detailed clinical characteristics and outcome listed on Table. Conclusions: For patients with locally advanced or metastatic UC who desired bladder preservation, platinum-based chemotherapy followed by EV with or without pembrolizumab showed encouraging CR and PFS and deserves to be explored further. [Table: see text]
The comprehensive analysis of relationship between gut microbiome and treatment outcome of androgen deprivation therapy (ADT)-based treatment in patients with metastatic castration-sensitive and -resistant prostate cancer.
Authors: Nobuaki Matsubara, Shunsuke Sakai, Riu Yamashita, Toshihiro Misumi, Masaki Shiota, Masatoshi Eto, Taigo Kato, Takahiro Osawa, Takashige Abe, Nobuo Shinohara, Koshiro Nishimoto, Yota Yasumizu, Nobuyuki Tanaka, Mototsugu Oya, Takao Fujisawa, Satoshi Horasawa, Yoshiaki Nakamura, Takayuki Yoshino, Norio Nonomura
Journal: Journal of Clinical Oncology (2023)

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.
Prognostic role of geriatric assessment (GA) in patients with metastatic prostate cancer (MPCaP) attended in medical oncology.
Authors: Regina Girones, Maria Arnal, Silvia Forcano
Journal: Journal of Clinical Oncology (2023)

90 Background: The Geriatric Assessment (GA) represents the future of the geriatric oncology to reduce toxicities and treatment-related hospitalization in the elderly. It has demonstrated results in predicting chemotherapy feasibility and response to docetaxel in patients with metastatic castration-resistant prostate cancer (MCRPca) (Della pepa). GA has also been explored in patients suitable to oral treatment (ref). In order to understand the prognostic capabilities of GA, we developed this analysis. Methods: All patients with MPCa sent to evaluation for Medical Oncology from January 2020 to August 2022 were analysed. GA was applied to those with 70 years or more. A geriatrician and/or an oncologist performed the evaluation. Informed consent was signed for patients. Ethical committee approved the protocol. Results: 85 patients were sent to Medical Oncology, 40 young (40%), 51 elderly (50%). Median age for young patients was 62 (46-68) and 79 for elderly (70-91). A comparison between populations is shown. This was an observational prospective study involving 51 patients who were 70 years of age or older. We performed GA including five domains and divided our patients into “fit”, “lower frailty,” and “high frailty” using Rockwood frailty scale. The relation between GC group and overall survival was explored. After GA, 26 were fit (51%), 16 had lower frailty (30%) and 10 had high frailty (19%). We found a statistically significant relationship between GA group and overall survival. Fit patients had overall survival of 27,1 months (22,8-31,5) versus 15,1 months (9,7-19,4) for low frailty and 5,6 months (3,2-7,9) for high frailty (p;0,000). Conclusions: Although our analysis has a selection bias as we only explored elderly patients sent to Medical Oncology, we found that a GA may help clinicians to recognize frail patients, and hence to reduce toxicities and early treatment discontinuation. We demonstrate its capability to be incorporated into routine clinical practice. [Table: see text]
Association of whole blood mRNA expression and overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Akeem Ronell Lewis, Carlos Sosa, Olivia Bobek, David W. Hillman, Brian Addis Costello, Fernando Quevedo, Lance C. Pagliaro, Richard M. Weinshilboum, Junmei Cairns, Leiwei Wang, Krishna Rani Kalari, Manish Kohli, Winston Tan, Karthik Giridhar
Journal: Journal of Clinical Oncology (2023)

201 Background: Previous studies have evaluated peripheral whole blood mRNA to identify prognostic biomarkers in metastatic prostate cancer, with no consistent genes of prognostic significance between studies and sample collection done at various points of therapy. We aim to identify the prognostic value of 20 previously identified genes in patients mCRPC from a prospective clinical trial. Methods: Between June 2013 and August 2015, whole blood was prospectively collected in PAXgene RNA tubes from 92 men with mCRPC (NCT01953640). Gene expression from samples with RIN &gt; 4.0 were quantified using a customized NanoString CodeSet of 20 candidate genes (C1QA, MCM2, STOM, GABARAPL2, R10K3, HMBS, TFDP1, CDKN1A, ITGAL, TMCC2, TERF2IP, MMP9, SNCA, TIMP1, SLC4A1, SELENBP1, TMEM66, SEMA4D, PROS1, CD22). The raw data from the nCounter Analysis system were normalized to the positive controls and log2 transformed. Univariable Cox proportional hazards models were performed on each target gene sufficiently above negative control (5 times the maximum value of the negative control) to evaluate associations with overall survival (OS). For each gene we considered a linear, quadratic, or categorical model with quantile cutpoints. Categorical models with cutpoints at the 25th percentile for the genes CD22, GABARAPL2, R10K3, and STOM were used as there was a nonlinear relationship between gene expression and death hazard. The remaining genes were modeled with a linear model. Findings were considered statistically significant based on p-values adjusted using the Holm-Bonferroni correction. Results: 18/20 genes were identified and passed quality control (QC) measures, which excluded C1QA and MCM2. 72/92 men had an evaluable pretreatment specimen that passed QC. The median age was 72 years. The study cohort was evenly balanced in terms of Gleason score ( &lt; = 7 v. &gt; 7) and 60% had high volume disease. The median follow-up time was 5.73 years (IQR: 5.39, 6.49) and 58 patients had died. Of the 18 genes evaluated, STOM (Stomatin) [hazard ratio (HR) 3.00, adjusted p = 0.007] and GABARAPL2 (GABA Type A Receptor Associated Protein Like 2) [HR 2.62, adjusted p = 0.033] were significantly associated with overall survival in univariate analysis. In multivariate analysis, after adjusting for volume of metastatic disease and Gleason score, STOM [HR 2.89, adjusted p = 0.014] was significantly associated with overall survival. Conclusions: Elevated whole blood mRNA expression of STOM is adversely associated with OS in mCRPC. Further studies investigating elucidating the molecular significance of STOM in mCRPC are planned. Clinical trial information: NCT01953640 .
A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis).
Authors: Girish S. Kulkarni, Kyle A Richards, Peter C. Black, Ricardo A. Rendon, Joseph Chin, Neal D. Shore, Gautam Jayram, Eugene V. Kramolowsky, Daniel Saltzstein, Piyush K. Agarwal, Laurence Belkoff, Michael A. O'Donnell, Ashish M. Kamat, Michael A.S. Jewett, Donald L. Lamm, Victor DeGruttola, Arkady Mandel, Roger Dumoulin-White, Wassim Kassouf
Journal: Journal of Clinical Oncology (2023)

528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm 2 ) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]
Validation of AGR2 and KRT19 as specific proteins being significantly and differentially expressed in teratoma compared to necrosis in retroperitoneal lymph node resections after chemotherapy (pcRPLND).
Authors: Tim Nestler, Lara Kremer, Melanie von Brandenstein, Maike Wittersheim, Svenja Wagener-Ryczek, Pia Paffenholz, Stefan Mueller, Alexander Quaas, Martin Hellmich, Margarete Odenthal, David Pfister, Axel Heidenreich
Journal: Journal of Clinical Oncology (2023)

412 Background: Metastatic non-seminomatous testicular tumor patients with residual retroperitoneal tumor masses &gt; 1cm after chemotherapy are treated with pcRPLND. The goal of pcRPLND is to remove viable tumors (V) and teratoma (T), which are present in approximately 10% and 40% of cases, respectively. However, histopathologically, only scar/necrosis (N) is identified in the remaining 50% of patients. In those patients, surgical therapy is not necessary, resulting in a relevant overtreatment. So far, no adequate distinction between the histologies exists preoperatively. Recently, the first biomarker was described with miR371a-3p in serum, which is highly specific for V, but not for T. In 2022 we reported AGR2 and KRT19 to be significantly and differentially expressed in teratoma compared to necrosis in pcRPLND tissue on protein and mRNA level. The aim of this study was to validate these proteins on an independent cohort. Methods: All consecutive pcRPLND patients from 2021 who were treated in the University Hospital of Cologne, Germany, were selected (n=66). All patients had residual masses &gt; 1 cm and normalized or plateaued tumor markers. For immunohistochemistry, the monoclonal antibodies KRT19 and AGR2 were applied to representative Formalin-Fixed Paraffin-Embedded tissue. To quantify the results, the H-score was used. The investigators were blinded to the final pathohistological results. Results: The cohort was composed of 66 patients, 23 patients with T, 24 patients with V and 19 patients with N. Significantly higher H-scores were shown for AGR2 and KRT19 when comparing T vs. N and T vs. V (both p &lt; 0.0001). The discriminatory ability of the two proteins AGR2 and KRT19 was calculated by AUCs for T vs. N and was 1.0 in each case with a corresponding sensitivity and specificity for T of 100%. Conclusions: With AGR2 and KRT19, we could validate the two proteins that are significantly and differentially expressed in the pcRPLND specimen in the clinically relevant groups T vs. N. In perspective, these proteins could be targeted by radiolabeled ligands as a tracer in order to reliably distinguish patients with teratoma from those with necrosis by means of functional imaging. Thus, overtreatment with pcRPLND of patients with N could be safely reduced.
Real world outcomes of patients with non-clear cell renal cell carcinoma: A single Asian centre experience.
Authors: Johan W.K. Chan, Daniel Peh, Wei Chong Tan, Hui Shan Tan, Quan Sing Ng, Tanujaa Rajasekaran, Yi Lin Teh, Stephanie Saw, Wan Ling Tan, Gillianne Lai, Amit Jain, Ravindran Kanesvaran
Journal: Journal of Clinical Oncology (2023)

632 Background: Non-clear cell RCC (nccRCC) represents a heterogenous group of tumors which is less well studied than clear cell RCC. Clinical data supporting the treatment of nccRCC are still based on phase 2 studies and clinical trials conducted in ccRCC. Little is known about this group of patients in Asia. In this study, we aim to report the real world outcomes of nccRCC patients in a cancer centre in Singapore. Methods: We conducted a retrospective analysis on 81 non-clear cell RCC patients treated at the National Cancer Centre Singapore from 2007-2022. Data on patient demographics, disease characteristics, treatment outcomes and adverse events were collected retrospectively up till March 2022. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Responses to treatment were recorded based on RECIST v1.1 and analyzed using logistic regression. Results: 81 patients were included in this analysis, with a median age at diagnosis of 57 years old. Papillary RCC accounted for 32% (n=26) of the cases, chromophobe RCC was 2% (n=2), unclassified RCC was 28% (n=23), and other subtypes was 20% (n=24). Sarcomatoid features were present in 8% (n=10). Median follow-up time was 24 months. Among this cohort, 73 patients (90%) received tyrosine kinase inhibitors (TKI) alone, 8 patients (9%) had immunotherapy with VEGF TKI while 4 patients (4%) underwent dual checkpoint inhibitors. Median OS for the cohort was 19.4 months, while median PFS was 16 months. Overall disease control rate rate (CR/PR/SD) for first-line treatment was 60%. Comparison of outcomes shown below. Conclusions: This real-world Asian study provides important data regarding clinical outcomes in this rare and heterogeneous group of non-clear cell RCC patients. OS in nccRCC remains inferior to ccRCC and is comparable to data reported in Western populations [Table: see text]
Distinct gene expression patterns identify patients who relapse after neoadjuvant pembrolizumab and radical cystectomy in the PURE-01 study.
Authors: Moritz Johannes Reike, Daniele Raggi, Laura Marandino, Damiano Alfio Patanè, Emanuele Crupi, Tiago Costa de Padua, Peter C. Black, Ewan Gibb, Andrea Necchi
Journal: Journal of Clinical Oncology (2023)

549 Background: The PURE-01 clinical trial reported the use of neoadjuvant treatment with pembrolizumab prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC; cT2–3N0M0; PMID 30343614). We have previously reported that specific molecular subtypes (i.e. basal or claudin-low) and immune signatures are associated with more favorable survival. However, reports on the detailed tumor biology of patients (pts) who relapsed after neoadjuvant pembrolizumab are lacking. Herein, we provide a detailed characterization of relapsing pts and identify distinct gene expression patterns with potential utility as novel biomarkers. Methods: Microarray data from transurethral resection of the bladder tumor (TURBT; N=102) and matched RC (N=25) tissue from the PURE-01 trial were analyzed. Gene expression signatures and molecular subtypes were assigned as previously described (PMID 32165065). The Kaplan-Meier method was used to estimate differences in patient outcomes. Immune-signatures were split by median for survival analysis. All significance testing used a two-sided t-test at a threshold of 0.05. Results: Differential gene expression analysis identified KRT20 and H19 to be enriched in relapsing patients (both p&lt;0.001). Expression below the median was predictive of favourable 3-year overall (OS) and recurrence-free (RFS) survival (OS, 37.3% vs. 21.6%, p=0.118; RFS, 35.3% vs. 21.6%, p&lt;0.01 and OS, 41.2% vs. 17.6%, p=0.03; RFS, 39.2% vs. 17.6%, p=0.012, respectively). Distribution of molecular subtypes showed tumors with neuronal character (NE-like) were enriched in pts who relapsed. Low immune-signatures, including Interferon-gamma and -alpha, were predictive of relapse (3-year RFS, 31.4% vs. 25.5%, p&lt;0.001 and 31.4% vs. 25.5%, p&lt;0.01, respectively), whereas Immunophenoscore for CD4 was not. None of these markers were predictive for relapse in matched RC-samples. Conclusions: Relapsing patients demonstrated distinct biological patterns in pre-therapy tumor samples that show prognostic value, potentially making an earlier identification and therefore adapted treatment possible. Low expression of immune-related signatures was associated with relapse.
Adrenocortical carcinoma: Report of data from 66 patients with a rare disease at a cancer center.
Authors: Rafael Haikal dos Santos Abduch, Milena Shizue Tariki, Maria Nirvana Formiga, Stephania Martins Bezerra, Giovana Tardin Torrezan, José Augusto Rinck
Journal: Journal of Clinical Oncology (2023)

1 Background: Adrenocortical carcinoma (ACC) is a rare (1,02 per million population) disease with unfavorable prognosis. In Brazil, the incidence is about 15 times higher than in the rest of the world, mainly due to significant prevalence of the TP53-R337H germline mutation in this population. Methods: We performed a retrospective analysis of 66 patients diagnosed with ACC at AC Camargo Cancer Center. Clinical, pathological, epidemiological, treatment and survival data were collected from the patient’s chart and described. Results: Between 2004 and 2021, 66 patients were diagnosed with ACC. The median age was 45 years and 56% were female. 23 (35%) patients had at least one first-degree relative with a history of cancer and 8 (12%) had a second primary tumor. Ten patients were tested for Li-Fraumeni Syndrome and 30% went positive (TP53- R337H germline mutation). Two of them had first-degree relative with cancer. In our cohort, 22 (33%) patients were stage IV, 14 (21%) stage III, 19 (29%) stage II, 6 (9%) stage I and 5 (7%) unknown stage. 36% of tumors were considered functional (cortisol and/or androgens). At 50 months the estimated OS was 25,9% in the metastatic group and 83% in the localized group (p&lt;0.0001). Among localized patients, 13 (29%) received adjuvant mitotane and 31 (70%) were followed without mitotane. The 12-month DFS rate was 50,8% in the mitotane group versus 67,8% in the group without mitotane (p = 0.83). The Ki67 index was performed in 20 localized patients. The 12-month DFS rate was 58,2% in the high Ki67 index (&gt;10%) group versus 75% in the low ki67 index (≤10%) group (p = 0.47). In metastatic scenario 31 (47%) underwent systemic treatment and the most common (71%) first line chemotherapy was EDP (etoposide-doxorubicin-cisplatin) plus mitotane with an objective response rate of 27% and 56% of them had progression of disease as the best response to treatment. 14 patients received second line and 7 received third line treatment. Gemcitabine-capecitabine,cisplatin-based and Pembrolizumab were the most common regimens used in advanced lines. Conclusions: ACC has a poor prognosis and a significant prevalence of personal and family history of cancer. EDP-mitotane was the preferred regimen used as the first line treatment. As a rare disease, worldwide data can add evidence for future improvements in adrenal cancer.